POS1024 TOFACITINIB TREATMENT AMELIORATES MUSCLE LOSS IN COLLAGEN-INDUCED ARTHRITIS MODEL
Authors: R. Cavalheiro Do Espírito Santo, T. Hein Da Rosa, B. Bartikoski, M. Farinon, R. T. Pedo, M. L. Gasparini Vieira, T. Karnopp, G. Chapacais, A. DI Domenico, S. Loch, M. Dos Santos, L. Santos, J. Miranda de Souza Silva, R. Xavier
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Sarcopenia is a muscle disease characterized by reduction of muscle strength and muscle mass. In RA, 25.9 to 43.3% of the patients present sarcopenia [1]. The loss of muscle mass observed in RA patients occurs either by activation of catabolic pathways or by inhibition of anabolic pathways [2]. Despite having a list of drugs capable of treating RA inflammation, the effect of these therapeutic interventions on muscle are not elucidated [3]. <h3>Objectives</h3> To evaluate the effect of tofacitinib on muscle mass of collagen-induced arthritis (CIA) mice. <h3>Methods</h3> CIA was induced in male DBA/1J mice. Animals were randomized into 3 groups: I) CIA + tofacitinib (CIA-TOF; n=10); II) CIA + vehicle (CIA-VEH; n=10); III) healthy controls (CO; n=9). Vehicle (PBS) or tofacitinib 15mg/kg were administered twice a day, between days 18 and 45 after the disease induction. Clinical score, edema and body weight were evaluated during the experimental period. After euthanasia, tibio-tarsal joints were collected for assessment of disease histopathological score, and tibialis anterior (TA) and gastrocnemius (GA) muscles were weighed to assess muscle mass. Muscle atrophy was evaluated by measurement of TA myofiber cross-sectional area (CSA). Expression of proteins related to muscle regeneration or catabolism (Pax7, MyoD, myogenin and Murf-1) were evaluated by western blot in GA homogenates. Serum inflammatory markers (TNF and IL-6) were evaluated by ELISA. Statistical analysis included ANOVA followed by Tukey's or with Kruskal-Wallis. The statistical difference was assumed for p&lt;0.05. <h3>Results</h3> As expected, tofacitinib treatment decreased arthritis severity by reducing clinical score (p=0.03) and hind paw edema (p=0.04) in comparison with CIA-VEH group. CIA-TOF showed weight gain (p=0.02), higher TA (p=0.009) and GA (p=0.02) weights, and increased CSA compared to CIA-VEH group (p=0.01). On day 45, CIA-TOF presented increased muscle strength compared to CIA-VEH group (p=0.006), however, no difference was found in the fatigue parameter among groups (p&gt;0.05). The expression of Pax7 was unchanged (p=0.07), while MyoD expression showed an increase trend, and myogenin expression was significantly increased in CIA-TOF compared to CIA-VEH (p=0.04) and CO groups (p=0.02). The treatment did not significantly modify Murf-1 expression. Compared to CIA-VEH group, CIA-TOF mice showed decreased serum levels of TNF (p=0.04), and no difference in IL-6 serum levels (p=0.08). <h3>Conclusion</h3> Tofacitinib attenuated muscle loss in arthritic mice, as increased muscle weight and muscle CSA were detected in treated mice. Additionally, an increased activation of satellite cells regeneration, based on the expression of myogenin, is a potential mechanism involved in tofacitinib-protection against muscle loss. <h3>Reference</h3> [1] Li TH et al.Semin Arthritis Rheum. 2021;51(1):236-245; (2) Hanaoka BY et al. Arthritis Care Res (Hoboken). 2019;71(2):173–7; (3) Hein TR et al. Arthritis Res Ther. 2022; 19;24(1):1 <h3>Acknowledgements</h3> PANLAR, CNPQ, CAPES, FIPE/HCPA. <h3>Disclosure of Interests</h3> Rafaela Cavalheiro do Espírito Santo: None declared, Thales Hein da Rosa: None declared, Bárbara Bartikoski: None declared, Mirian Farinon: None declared, Renata Ternus Pedo: None declared, Maria Luísa Gasparini Vieira: None declared, Thaís Karnopp: None declared, Gustavo Chapacais: None declared, Andressa Di Domenico: None declared, Sofia Loch: None declared, Manuela dos Santos: None declared, Leonardo Santos: None declared, Jordana Miranda de Souza Silva: None declared, Ricardo Xavier Grant/research support from: Pfizer Grant 60289911